S-cyclohexenylalkylhydantoins



Patented July 6, 1937 UNITED STATES PATENT, OFFICE 5,5-CYCLOHEXENYLALKYLHTDANTOINS AND THEIR MANUFACTURE August Binkert, Basel, Switzerland, assignor to the firm of Chemical Works, formerly Sandoz,

Basel, Switzerland No Drawing. Application September 25, 1935,

Serial No. 42,139. 1934 wherein R represents a CN and CON H2 group, with hypohalogenides in presence of an alkali and water, new 5.5rcyclohexenylalkylhydantoins of the general formula:

. 7 alkyl \O4O3NH can be obtained.

The 5,5 cyclohexenylalkylcyanoaceticand -malonic acid derivatives that are used as starting products in the present process can be prepared for instance by treating Adj-cyclohexenylalkylcyanoacetic acid ester with ammonia, whereby A-1,2 cyclohexenylalkylcyanoacetamides will be obtained, which yield on treatment with hypohalogenides in presence of an alkali and water the desired hydantoins.

The treatment of the compounds of the general formula:

cyclohexenyl R alkyl 0 ONE:

wherein R represents a CN and CONHz group with hypohalogenides in order to obtain the hydantoin derivatives can be carried out at a temperature of 0 to 100 C. preferably at 10-60 C. This treatment is generally carried out with aqueous solutions of alkalimetalhypohalogenides such as sodium and potassium hypochlorites or hypobromites-whereby also mixtures of different hypohalogenides such as'a mixture of sodium hyp-obroe mite-and calcium hypobromite can be used.

The concentration of the hypohalogenide solution may vary within wide limits, but it is advisable to employ 10 to 30% solutions of freshly prepared hypohalogenides. The treatment with hypohalogenides is preferably carried out in presence of'a water soluble alkaline compound, such as sodium and potassium hydroxides, carbonates and bicarbonates, but it is also possible to use as acid binding agent earth alkalimetal carbonates In Switzerland October 8, 12 Claims. (01. 260-124) and hydroxides in admixture with the above cited water soluble alkaline compounds.

The hydantoins prepared as above described generally remain dissolved in the aqueous solution if an excess of alkali is present therein, as they form water soluble alkalimetal salts. They can therefore be isolated in form of free hydantoins by treating their aqueous alkaline solutions with acids, or they can be isolated as alkalimetal salts by adding to their solution a suflicient amount of an organic solvent or a mixture of organic solvents such as methanol, ethanol or mixtures of these solvents with ether, chloroform and the like.

The 5,5-cyclohexenylalkylhydantoins prepared in this manner possess the general formula:

cyclohexenyl NH-O O e alk O NH in which the term cyclohexenyl represents a cyclohexenyl group such as the A-LZ-cyclohexenyl-,the A-2,3-cyclohexenyl-,the 4-methyl- A-1,2 cyclohexenyl group; The term alkyl represents a saturated or an unsaturated alkyl-group such as methyl, ethyl, propyl, butyl, allyl, bromallyl. These compounds are White tasteless and odourless crystalline products, easily soluble in organic solvents. They yield easily water soluble alkalimetal salts and can be used'as free hydantoins or as their water soluble salts for therapeutical application.

By treating the 5,5-cyclohexenylalkylhydantoins with alkylating and aralkylating agents, they become transformed into their monoor di- N-alkylor N-aralkyl derivatives; which also represent valuable products for therapeutical application.

These monoor di-N-alkylor -aralkyl derivatives of 5,5-cyclohexenylalkylhydantoins are preferably prepared by direct alkylation or aralkylation of 5,5-cyclohexenylalkylhydantoins by means of a treatment of these compounds with alkylating agents such as halogen-alkyls, dialkylsulphates, toluenesulph'onic acid esters, or aralkylhalogenides, such as for instance ethyl-bromide, methylchloride, dimethylsulphate, p-toluene-sulphonic acid propylester, benzylchloride, nitrobenzylchloride.

By means of this treatment a first alkyl or aralkyl group is introduced into the nitrogen atom in position 3, Whilst only later a second alkyl or aralkyl group is introduced into the nitrogen atom in position 1. This different reactibility of the nitrogen atoms affords the possibility of introducing different alkyl or aralkyl groups into the hydantoin ring.

The alkylation or aralkylation of 5,5-cyclohexenylalkylhydantoins may be carried out in a solvent or in presence of a diluting agent, whereby water, methanol, ethanol, acetone, ether or benzene can be used.

It is preferable to carry out the alkylation or aralkylation process in presence of acid binding agents such as sodium carbonate, sodium bicarbonate, sodium hydroxide, calcium carbonate or hydroxide, or organic bases such as pyridine, quinoline, dimethylaniline.

This process may further be carried out in open or closed vessels; sometimes it is advantageous to work under pressure and at temperatures up to 150 C. But generally it is possible to carry out the alkylation or aralkylation already at lower temperatures say from 20 C. upward. The temperature of alkylation is dependent of the alkylating or aralkylating agents used; some of them react already at low, others only at a higher temperature.

Further it is preferable to carry out the process under good stirring in order to obtain an intimate contact of the different products brought to reaction.

The new monoor di-N-alkylor aralkylor N-alkyl-N-aralkyl 5,5 cyclohexenylalkylhydantoins prepared in this manner possess the general formula:

I ioo wherein R represents an alkyl or a benzyl group and R represents hydrogen, an alkyl or a benzyl group, whereby R and R can be the same or different groups such as methyl, ethyl, propyl, butyl, isobutyl, allyl, bromallyl, benzyl, nitrobenzyl and halogenbenzyl.

In the dry state they are colorless, crystallized compounds without smell and taste. Generally they are easily soluble in ethanol, methanol, acetone, chloroform, difficultly soluble in cold, but soluble to some extent in hot water.

The 3-alkyland aralkyl-5,5-cyclohexenylalkylhydantoins are soluble in sodium hydroxide solutions, whereas the N-dialkylor -aralkyl derivatives are no more soluble therein.

All of the 5,5-cyclohexenylalkylhydantoins prepared as hereinabove described behave as unsaturated compounds on treatment with bromine or potassium permanganate.

In order to prepare the water-soluble alkalimetal salts of the 5,5-cyclohexenylalkylhydantoins and their N-monoalkylor -aralkyl derivatives, the freehydantoins are for example dissolved in a suitable organic solvent such as ethanol and treated with an equivalent quantity of sodium or potassium alcoholate, whereby the sodium or potassium salts of the hydantoin separate generally in a crystalline form. By filtration and washing with ethanol and ether, they can be obtained in a very pure form. It is obvious that the same salts can also be prepared by dissolving the above named hydantoins in a solution of sodium or potassium hydroxide and by evaporation of the solution preferably in vacuo, or by adding to this solution a certain amount of a suitable organic solvent, such as methanol or ethanol, whereby the salts become precipitated and can be separated in the usual manner.

cyclohexenyl The alkalimetal salts of the 5,5-cyclohexenylalkylhydantoins and of their N-monoalkylor aralkyl derivatives are colourless compounds, which can be used for therapeutical purposes.

An object of the present invention is therefore a process for the manufacture of 5,5-cyclohexenylalkylhydantoins characterized in that compounds of the general formula:

cyclohexenyl R alkyl CONH2 wherein R represents a CN and CONHz group, are treated with hypohalogenides in presence of alkali and water.

A further object of the present invention is a process for the manufacture of N-monoand dialkylor aralkylor N-alkyl-N-aralkyl-5,5- cyclohexenylalkylhydantoins of the general formula:

i cyclohexenyl\ /I1I 300 5 4 4 alkyl \CONR' wherein R and. R represent alkyl and benzyl groups and wherein R can also represent a hydrogen, which is characterized in that 5,5-cyclohexenylalkylhydantoins are treated with alkylating and aralkylating agents.

A further object of the present inventionis a process for the manufacture of water-soluble salts of the 5,5-cyclohexenylalkylhydantoins and their N-monoalkylof benzyl derivatives, consisting in treating the said hydantoins with an alkali of the alkalimetal series.

Still another object of the present invention are the 5,5-cyclohexenylalkylhydantoins of the general formula:

3 alkyl CO-NR wherein R and R represent hydrogen, alkyland benzyl groups, whereby if R represents hydrogen, R must also represent hydrogen, said products being colourless compounds without smell and taste, soluble in methanol, ethanol, acetone and chloroform and, when R represents hydrogen, also soluble in aqueous alkaline solutions yielding water-soluble alkalimetal salts.

Still another object of the present invention are the water-soluble alkalimetal salts of the 5,5-cyclohexenylalkylhydantoins and their 3'- alkylor benzyl compounds.

The following examples, without being limitative, illustrate the present process, the parts being by weight or by volume.

Example 1 35.6 gr. of A-1,2- cyclohexenylmethylcyano acetamide are introduced at G. into asodium hypobromite solution prepared from 11 com. of

bromine and 200 com. of a aqueous sodium hydroxide solution. After the solubilization of the compound has occurred, the solution is heated half an hour on the steam bath, allowed to cool down and diluted with 200 com. of water. After addition of some sodium bisulphite solution in order to eliminate the excess of hypobromite, the solution is acidulated with hydrochloric acid, whereby the 5,5-(A42) -cyclohexenylalkylhy-v dantoin precipitates with a nearly quantitative yield. By recrystallization from hot water the new compound will be'obtained in form of long colourless needles of M. P. 163-165 C. It is easily soluble in ethanol, acetone, chloroform, ether, dimcultly soluble in cold, but easier in hot water. It is soluble in aqueous solutions of alkalimetal hydroxides and-carbonates, yielding water soluble alkalimetal salts, and .can be precipitated therefrom in an unaltered form on addition of an acid. Potassium permanganate and bromine solutions become decolored on addition of the compound,-,which indicates its unsaturated character. r

0.2457 gr. thereof useaccording to the Ifieldahl method 25.34 ccm. organ-meal, which represents for the compound of the formula CmHmOzNz a nitrogen content of: N=14.43% calculated; N=14.45% found.

Example 2 If in the preceding example the A-1,2-cyolhexenylmethylcyanoeacetamide is replaced by the equivalent quantity of A-1,2cyclohexenylethylcyano-aoetamide (38.4, gr.) while otherwise there is proceeded as above described,-the 5,5-(A-1,2) cyclohexenylethylhydantoin -w ill be obtained. The same gives colourless crystals of M. P. 194-196 C. and is easily soluble in ethanol, acetone, chloroform, more difi'icultly in ether and difficultly soluble in petrol ether. The new compound is also difiicultlyvsoluble in hot and in cold Water, but easily soluble in sodium carbonate or hydroxide solutions. If treated as aqueous suspension with potassium permanganate it becomes immediately oxidized.

0.3807 gr. of the substance use according to the Kjeldahl'method 36.04 com. 1 6-nHzS04, which represents for the formula C11H1602N2 a nitrogen content of: V

N=13.46% calculated;

N=13.26% found.

Example 3 By replacingthe A -1,2-cyclohexanylmethylcy- ;ano-acetamide used in the Example 1 by an equivalent quantity of A-1,2-cyclohexenylallylcyano acetamide (40.8 gr.) and working. as therein described, the 5,5-(A-1,2) -cyclohexenylallylhy-dantoin will be obtained nearly with a; quantitative yield. This compound crystallizes in form of colorles s prismatic crystals of M. P. 178-17 9 C. and is easily soluble in-ethanol, methanol, acetone, chloroform, more difiicultlysoluble in benzene andether, difiicultly soluble in petrol ether. It is also difilcultly soluble in cold, but is soluble to some extent in hot water. In presence of sodium carbonate and hydroxide it is easily soluble in water yielding the sodium salt. In aqueous suspension it is immediately oxidized by potassium permanganate and on treatment with bromine it adds bromine very rapidly.

Example 4 method 55.31 ccm. of -n-H2SO4 for C1zH1sO2N2:

ethanol, chloroform, ethylacetate, more difficultly in ether, diflicultly soluble in petrol ether. It is nearly insoluble in sodium hydroxide solutions. Towards bromine and potassium permanganate it behaves as an unsaturated compound.

0.3024 gr. of this compound use according to the Kjeldahl method 29.10 ccm. of %-n-HzSO4, for C11H1sOzN2:

calculated; r N=13.48% found. If instead of dimethylsulphate an equivalent quantity of ethylbromide or allylbromide or ben zylchloride is employed and the treatment is carried out in an ethanol solution, the respective 3-ethylor -a1lylor -benzyl compounds will be 15 obtained.

Example 5 r By replacing in the Example 4 the 5,5-(A 1,2)

Towards potassium permanganate and 0.2683 gr. of the substance use by the Kjeldahl N: 12.61 calculated; N: 12.93% found.

Example 6 20.8 gr. of 3-methyl-5,5-(A-1,2)-cyc1ohexenylmethylhydantoin are dissolved. in 150 com. of ethanol and 15.0 ccm. of a sodium hydroxide solution and treated at 60-70" C. under good stirring with 19.5 gr. of dimethylsulphate. The reaction mixture must react Weakly alkaline at the'end of the methylation. After standing for about an hour, the ethanol is evaporated in vacuo and the residue mixed with water, whereby an oily'substance, that becomes hard after a certain time, will be obtained. This crystalline mass is then separated, ground with water, filtered and'dried. 'By recrystallization from petrol ether the 1,3-dimethyl 5,5-(A 1,2) -cyclohexenylmethylhydantoin will be obtained in form of colourless columns of M. P. 64-66" C. It is very easily soluble in ethanol, chloroform, ethylacetate, ether, more diflicultly soluble in petrol ether and very difiicultly soluble in water. potassium permanganate it behaves as an unsaturated compound.

Towards bromine and 0.6096 gr. of the substance use by the. Kjeldahl N=12.6l% calculated; N=12.71% found. The same compound will also be obtained by methylating the 5,5- (A-1,2) -cyclohexenylmethylhydantoin in an aqueous or ethanol solution in the manner described in Example 4, but using a 2 times greater quantity of sodium hydroxide and of dimethylsulphate.

By using in this example instead of dimethylsulphate an equivalent quantity of ethylbromide or allylbromide or benzylchloride the respective B-methyl-l-ethylor -a1lylor -benzyl compounds will be obtained.

Eatample 7 1 the 3-methyl-5,5- A-1,2) -cyclohexenylethylhydantoin (22.3 gr.) can be transformed into the 1,3-dimethyl 5,5 ,(A-l,2) -cyclohexenylethylhydantoin. This compound crystallizes in form of colourless plates of M. P. 65-67 C. It is very easily soluble in ethanol, acetone, ethylacetone, chloroform, soluble in ether and petrol ether, but insoluble in water. Towards bromine and potassium permanganate it behaves as an unsaturated compound.

0.5065 gr. of the substance use by the Kjeldahl method 42.49 ccm. of -n-HzSO4 for C10H20O2N2:

N=11.86% calculated;

N=11.75% found.

This compound can also be prepared in on operation by direct methylation of 5,5-(A-1,2-) cyclohexenylethylhydantoin in an aqueous or alcoholic solution if greater quantities of. the methylating agent are used.

What I claim is:'

1. A process for the manufacture of 5,5- (A- 1,2) -cyclohexenylalkylhydantoins, comprising treating the compounds of the general formula:

alkyl CONHz wherein the term alkyl represents one of the group consisting of saturated and unsaturated alkyl radicals and R represents oneof the group consisting of CN and CONHz radicals, with hypohalogenides in presence of water and of an alkali.

2. A process for the manufacture of 5,5- (A- 1,2) -cyclohexenylalkylhyclantoins, comprising treating the compounds of the general formula:

A-l, 2-cyclohexenyl R o alkyl CONHi wherein the term alkyl represents one of the group consisting of saturated and unsaturated alkyl radicals and R represents one ofthe group consisting of CN and CONT-I2 radicals, with hypohalogenides in presence of water and of analkali at a temperature of to 100 C. I

3. A process for the manufacture of 5,5- (A-l,2) -cyclohexenylalkylhydantoins', comprising treating the compounds of the general formula:

A-l, 2-cyolohexenyl R C alkyl \OONHQ wherein the term alkyl represents one of the group consisting of saturated and unsaturated alkyl radicals and R represents one of the group consisting of CN and CONHz' radicals, with hypohalogenides in presence-of water and of an alkali at a temperature of 0 to 100 C. and subjecting the 5,5-A-1,2-cyclohexenylalkylhydantoins thus obtained to a treatment with compounds capable of substituting the imino groups of the hydantoin ring and selected from the class consisting of alkylating and benzylating agents, this treatment being carried out in presence of solvents and acid binding agents at a temperature of 10 to 150 C.

4. A process for the manufacture of 5,5- (A-1,2) -cyclohexenylalkylhydantoins, comprising treating the compounds of the general formula:

A-l, 2-cyclohexenyl ON C -/v alkyl OONH:

wherein the term alkyl represents one of the group consisting of saturated and unsaturated alkyl radicals, with hypohalogenides in presence of water and of an alkali.

5. A process for the manufacture of 5,5- (A1,2) -cyclohexenylalkylhydantoins, comprising treating the compounds of the general formula:

A-l, 2-cyclohexenyl CN alkyl CONHi wherein the term alkyl represents one of the group consisting of saturated and unsaturated alkyl radicals, with sodium hypobromite in an aqueous medium and in presence of sodium hydroxide at a temperature of 0 to 100 C.

6. A process for the manufacture of 5,5- (A-1,2) -cyclohexenylmethylhydantoin, comprising treating A 1,2 cyclohexenylmethylcyanoacetamide with sodium hypobromite in an aqueous solution and in presence of sodium hydroxide.

7. A process for the manufacture of 5,5- (A 1,2) -cyclohexenylethylhydantoin, comprising treating A-1,2-cyclohexenylmethylcyano-acetamide with sodium hypobromite'in an aqueous solution and in presence of sodium hydroxide.

8. A process for the manufacture of 5,5- (A1,2) -cyclohexenylallylhydantoin, comprising treating A-1,2-cyclohexenylallylcyano-acetamide with sodium hypobromite in an aqueous solution and in presence of sodium hydroxide.

9. The A 1,2-cyclohexenylalkylhydantoins of the general formula:

A-l, 2-cyclohexenyl\ /l {-2C 0 o 5 3 alkyl CO-N-R' wherein the term alkyl represents one of the group consisting of saturated and unsaturated alkyl radicals and wherein R and R represent one of the group consisting of hydrogen, alkyl and benzyl, whereby if R represents hydrogen, R must also represent hydrogen, said products being colourless compounds without smell and taste, soluble in methanol, ethanol, acetone and chloroform and, when R represents hydrogen, also soluble in aqueous solutions yielding water soluble alkalimetal salts.

10. The 5,5-(A 1,2) cyclohexenylmethylhydantoin, which is a colourless crystallized compound without smell and taste, melting at 163-165 C., easily soluble in ethanol, acetone, chloroform and ether, soluble in hot water and in aqueous alkaline solutions yielding water soluble alkalimetal salts. v 11. The 5 ,5-(A-1,2)-cyclohexenylethylhydantoin, which is a colourless crystallized compound without smell and taste, meltingat 194-196" C., easily soluble in ethanol, acetone, chloroform and ether, soluble in hot water and in aqueous alkaline solutions yielding water soluble alkalimetal salts.

12. The 5,5-(A-1,2) -cyclohexenylallylhydantoin, which is a colourless crystallized compound without smell and taste, melting at 1'78179 C., easily soluble in ethanol, acetone, chloroform and ether, soluble in hot water and in aqueous alkaline'solutions yielding water soluble alkalimetal salts. v

- AUGUST BINKERT. 

